TGFβ1 protects cells from γ-IR by enhancing the activity of the NHEJ repair pathway.

UNLABELLED: Several groups have reported that TGFβ1 regulates cellular responses to γ-irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFβ1 in cellular responses to γ-irradiation was investigated in detail. The data indicate that TGFβ1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFβ1 was examined. Studies reveal that TGFβ1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFβ1-induced protection against IR. Overall, these data indicate that TGFβ1 facilitates the NHEJ repair process upon γ-irradiation and thereby enhances long-term survival. IMPLICATIONS: These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFβ signaling pathway. ©2014 American Association for Cancer Research.